[go: up one dir, main page]

WO2017044626A1 - Compositions d'humanine, méthodes et utilisation pour protéger le coeur contre le stress et la chimiothérapie - Google Patents

Compositions d'humanine, méthodes et utilisation pour protéger le coeur contre le stress et la chimiothérapie Download PDF

Info

Publication number
WO2017044626A1
WO2017044626A1 PCT/US2016/050780 US2016050780W WO2017044626A1 WO 2017044626 A1 WO2017044626 A1 WO 2017044626A1 US 2016050780 W US2016050780 W US 2016050780W WO 2017044626 A1 WO2017044626 A1 WO 2017044626A1
Authority
WO
WIPO (PCT)
Prior art keywords
humanin
cancer
tumor
therapeutic agent
subject
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2016/050780
Other languages
English (en)
Inventor
Christina Wang
Yanhe Lue
Ronald S. Swerdloff
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lundquist Institute for Biomedical Innovation at Harbor UCLA Medical Center
Original Assignee
Los Angeles Biomedical Research Institute at Harbor-Ucla Medical Center
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Los Angeles Biomedical Research Institute at Harbor-Ucla Medical Center filed Critical Los Angeles Biomedical Research Institute at Harbor-Ucla Medical Center
Publication of WO2017044626A1 publication Critical patent/WO2017044626A1/fr
Priority to US15/916,204 priority Critical patent/US10792331B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4711—Alzheimer's disease; Amyloid plaque core protein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals

Definitions

  • Cardiotoxicity occurs with cancer chemo- and targeted-therapy. The severity depends on the type of agent, the route of administration, acute/immediate or chronic related to cumulative dose, and underlying cardiac disease of the patient (Yeh, 2006; Yeh, et at , 2004).
  • Anthracylines Doxorubicin [DOX], Daunorubicin, Epirubicin, Idarubicin
  • DOX Doxorubicin
  • Acute cardiotoxicity manifests as ST segment changes and T wave abnormalities
  • chronic toxicity is dose related and presents as congestive heart failure and left ventricular dysfunction.
  • the incidence of congestive heart failure in DOX treated patients with cancer is 3 to 5% at a cumulative dose of 400mg/m 2 and 7 to 26% at a cumulative dose of 550mg/m 2 (Guo & Wong, 2014).
  • the mechanism of action may be due to generation of iron-related reactive oxygen species and binding to topoisomerase 2b to induce mitochondrial dysfunction (Berthiaume & Wallace, 2007; Gammella, et at , 2014; Wallace, 2003).
  • Doses of DOX >550mg/m 2 cause increased rates of cardiotoxicity and cardiomyopathy. The late cardiotoxicity causes increased morbidity and mortality in cancer survivor.
  • HN Humanin
  • a 24-amino acid mitochondrial derived peptide is an endogenous anti-apoptotic peptide in many tissues. HN is expressed in germ cells and Leydig cells in testes
  • HN reportedly protects against male germ cell apoptosis induced by testicular hormonal deprivation (Jia, et ai, 2013; Lue, et at , 2010).
  • HN has been proposed as an potential oncopeptide (Maximov, et al.
  • HN gene is expressed in cutaneous T-cell lymphoma (Hartmann, et ah , 2008), diffuse large B-cell lymphoma (Tarantul & Hunsmann, 2001), and gastric cancer (Mottaghi-Dastjerdi, et ah , 2014).
  • a method of reducing, decreasing, or inhibiting cardiotoxicity in a subject from an anti-cancer or anti-tumor therapeutic agent suppression or death where cardiotoxicity is induced, promoted, increased, or stimulated by the anti-cancer or anti-tumor therapy comprising administering to a subject prior to, during or after treatment with an anti-cancer or anti -tumor therapeutic agent an amount of humanin or a humanin analog sufficient to protect, reduce, decrease, or inhibit cardiotoxicity induced, promoted, increased, or stimulated by the anti-cancer or anti-tumor therapeutic agent.
  • a method of protecting or preserving cardiac function a subject administered an anti-cancer or anti-tumor therapeutic agent wherein cardiac function may be impaired by an anti-cancer or anti-tumor therapeutic agent.
  • a method includes administering to a subject prior to, during or after treatment with the anti-cancer or anti-tumor therapeutic agent an amount of humanin or a humanin analog sufficient to protect or preserve cardiac function in the subject.
  • a humanin or a humanin analog in the manufacture of a medicament 1) for reducing, decreasing, or inhibiting cardiotoxicity from a anticancer or anti-tumor therapeutic agent, or 2) for protecting or preserving cardiac function in presence of an anti-cancer or anti-tumor therapeutic agent, e.g. , in a subject administered an anticancer or anti-tumor therapeutic agent.
  • the anti-cancer or anti-tumor therapeutic agent comprises an alkylating agent, an anthracycline, an anti-metabolite, plant extract, plant alkaloid, nitrosourea, hormone, nucleoside or nucleotide analog.
  • the anti-cancer or anti-tumor therapeutic agent comprises a DNA intercalating agent or an agent that attaches or bonds to DNA.
  • the anti-cancer or anti-tumor therapeutic agent comprises Doxorubicin, Epirubicin, Idarubicin, Daunorubicin, Valrubicin, Mitoxantrone, Paclitaxel, Cisplatin, Carboplatin, Oxiplatin, Trastuzumab, Bevacizumab, Lapatinib, Alemtuzumab or Imatinib.
  • the anti-cancer or anti-tumor therapeutic agent is not Daunorubicin.
  • the humanin or a humanin analog does not substantially reduce, decrease, suppress or inhibit efficacy or activity of the anti-cancer or anti-tumor therapeutic agent.
  • the efficacy or activity of the anti-cancer or antitumor therapeutic agent comprises partial or complete destruction of a hyperproliferating cell, or a neoplastic, tumor, cancer or malignant cell mass, volume, size or numbers of cells; stimulating, inducing or increasing hyperproliferating cell or neoplastic, tumor, cancer or malignant cell necrosis, lysis or apoptosis; reduces hyperproliferating cell or neoplasia, tumor, cancer or malignancy volume size or cell mass; inhibits or prevents progression or an increase in hyperproliferating cell or neoplasia, tumor, cancer or malignancy volume, mass, size or cell numbers, reduces neoplasia, tumor, cancer or malignancy metastasis volume, size or cell mass; or prolongs lifespan.
  • a method or use reduces, decreases, or inhibits damage to cardiac cells or cardiac tissue. In some embodiments, a method or use reduces, decreases, or inhibits cardiac mortality of a subject. In some embodiments, a method or use reduces, decreases, or inhibits impairment of cardiac function caused or induced by the anti-cancer or anti-tumor therapeutic agent. In some embodiments, a method or use decreases, or inhibits impairment of cardiac function, for example, as determined by electrocardiogram, magnetic resonance imaging (MRI) or computerized tomography (CT) scan. In some embodiments, cardiac function impairment comprises decrease in ejection fraction and/or fractional ventricular shortening. In some embodiments, a method or use restores, stabilizes or inhibits or prevents a reduction or decrease in ejection fraction and/or fractional ventricular shortening caused or induced by the anti -cancer or anti-tumor therapeutic agent.
  • MRI magnetic resonance imaging
  • CT computerized tomography
  • humanin comprises the sequence:
  • humanin analog comprises the sequence: MAPRGFSCLLLLTGEIDLPVKRRA (HN-S14G; SEQ ID NO:2), or any sequence set forth in Tables 1-4.
  • the neoplasia, tumor, cancer or malignancy is metastatic, non- metastatic or benign. In some embodiments, the neoplasia, tumor, cancer or malignancy comprises a solid cellular mass. In some embodiments, the neoplasia, tumor, cancer or malignancy comprises hematopoietic cells.
  • the neoplasia, tumor, cancer or malignancy comprises a carcinoma, sarcoma, lymphoma, leukemia, adenoma, adenocarcinoma, melanoma, glioma, glioblastoma, meningioma, neuroblastoma, retinoblastoma, astrocytoma, oligodendrocytoma, mesothelioma, reticuloendothelial, lymphatic or haematopoietic neoplasia, tumor, cancer or malignancy.
  • the sarcoma comprises a lymphosarcoma, liposarcoma, osteosarcoma, chondrosarcoma, leiomyosarcoma, rhabdomyosarcoma or fibrosarcoma.
  • the haematopoietic cell neoplasia, tumor, cancer or malignancy comprises a myeloma, lymphoma or leukemia.
  • the neoplasia, tumor, cancer or malignancy comprises a metastatic melanoma.
  • neoplasia, tumor, cancer or malignancy comprises a lung, thyroid, head or neck, nasopharynx, throat, nose or sinuses, brain, spine, breast, adrenal gland, pituitary gland, thyroid, lymph, gastrointestinal (mouth, esophagus, stomach, duodenum, ileum, jejunum (small intestine), colon, rectum), genitourinary tract (uterus, ovary, cervix, endometrial, bladder, testicle, penis, prostate), kidney, pancreas, liver, bone, bone marrow, lymph, blood, muscle, or skin, lung, biliary tract, or hematologic neoplasia, tumor, or cancer.
  • the methods or uses further comprise administration or use of a second, third or fourth anti-cancer or anti-tumor therapeutic agent.
  • the humanin or humanin analog is administered or used prior to, substantially contemporaneously with or following administration of the anti-cancer or anti-tumor therapeutic agent.
  • the humanin or humanin analog is administered or used in combination with the anti-cancer or anti-tumor therapeutic agent.
  • the humanin or humanin analog is administered or used in one or more dose amounts of 0.05 to 50 mg/Kg per day.
  • humanin or the humanin analog is administered or used in one or more dose amounts of 0.1 to 25 mg/Kg per day, 0.5 to 15 mg/Kg per day, or 1.0 to 10 mg/Kg per day.
  • a subject has a hyperproliferative disease or disorder. In some aspects of the methods and uses the subject has a metastatic or non-metastatic neoplasia, tumor, cancer or malignancy.
  • the subject has undergone surgical resection, chemotherapy, immunotherapy, ionizing or chemical radiotherapy, local or regional thermal (hyperthermia) therapy, or vaccination.
  • the subject is or is not a candidate for surgical resection, chemotherapy, immunotherapy, ionizing or chemical radiotherapy, local or regional thermal (hyperthermia) therapy, or vaccination.
  • the subject is a mammal.
  • the subject is a primate.
  • the subject is a human.
  • FIG. 1 shows a schedule for mice treated with HNG, DOX or HNG+DOX.
  • FIG. 2 shows body weights (grams) of control, untreated, HNG treated mice increased weight, whereas DOX and HNG+DOX mice decreased weight with DOX losing significantly more weight (see inset).
  • Body weights (g) of control, untreated, HNG treated mice increased weight, whereas DOX and HNG+DOX mice decreased weight with DOX losing significantly more weight.
  • FIG. 3 shows mice treated with DOX had smaller hearts than non-treated and HNG treated mice, HNG +DOX had significantly higher heart weight than DOX alone group. When corrected by body weight, these differences were still observed.
  • FIG. 4 shows mice treated with DOX had lower ejection fraction and fractional shortening. Both parameters were improved by co-administration.
  • FIG. 5 shows an experimental design and treatment schedule. Echocardiograms were performed on 20 to 30 mice a day for 3 or 4 days on at week 4, 8 and 10. Animals were sacrificed at week 10.
  • Fig. 6 shows ejection fraction after treatment with Dox, HNG and DRZ alone or in combinations.
  • HN Humanin
  • HN and HN analogs can be used as agents to reduce, decrease, or inhibit cardiotoxicity caused or induced by an anti-cancer or antitumor therapeutic agent, and/or protect or preserve cardiac function in the presence of an anticancer or anti-tumor therapeutic agent.
  • HN and HN analogs were able to protect animals against chemotherapy induced cardiac impairment and limit/protect cardiac
  • cytotoxicity/damage caused by chemotherapy doxorubicin
  • doxorubicin cytotoxicity/damage caused by chemotherapy
  • methods, uses and compositions described herein can be used as an adjunct to treatments of hyperproliferative diseases and disorders, (e.g. , neoplasias, tumors, cancers and malignancies) in which cardiac function is impaired or cardiac cells are suppressed or killed by treatment with chemotherapy.
  • method and compositions herein can protect cancer patient from cardiac adverse acute chemotherapy effects.
  • method and compositions herein can protect or preserve a subject from treatment-induced cardiac function impairment and/or cardiotoxicity, which can lead to damage to cardiac cells or cardiac tissue and/or increase the risk of cardiac mortality.
  • a subject is any living or non-living organism, including but not limited to a mammal such as a human.
  • a subject can also be a non-human animal, non-limiting examples of which include a reptile, avian, amphibian, fish, ungulate, ruminant, bovine (e.g. , cattle), equine (e.g. , horse), caprine and ovine (e.g. , sheep, goat), swine (e.g. , pig), camelid (e.g. , camel, llama, alpaca), primate (e.g.
  • a subject may be any age (e.g. , an embryo, a fetus, infant, child, adult).
  • a subject can be of any sex (e.g. , male, female, or combination thereof).
  • a subject may be pregnant. In particular embodiments a subject is a human.
  • a subject is a human patient.
  • a patient can be any subject suspected of having, diagnosed with, or undergoing treatment for an ailment, disease or infection, or a subject who could benefit from a use or method herein.
  • a patient can be any subject suspected of having, diagnosed with, or undergoing treatment for an ailment, disease or infection, or a subject who could benefit from a use or method herein.
  • a patient is a subject diagnosed with a hyperproliferative disorder or disease, such as cancer and/or undergoing a treatment for a cancer.
  • Cardiac cells which may benefit from a treatment or use include any cell of the heart that contributes to the structure, function (mechanical/electrical) of the heart. Particular examples include cardiomyocytes (atrial and ventricular) which form the myocardium and cardiac fibroblasts. Additional cardiac cells include endothelial cells. Specialized cardiac cells include Pacemaker cells and Purkinje fibers in the conduction system that generate and conduct electrical impulses.
  • the sinoatrial node (SAN) which is composed of pacemaker cells, resides in the right atrium generating impulses to initiate heart contraction.
  • the atrioventricular node (AVN) located between the atria and ventricles, conducts an electrical impulse from the atria to the ventricles. Accordingly, cardiac damage or cardiac impairment may occur due to toxicity towards any one of such cells, or a combination thereof. As such, protection and/or preservation in accordance with the methods and uses herein may be directed towards any one of such cells, or a combination thereof.
  • suppression and grammatical variations thereof mean an adverse effect of an anti-cancer or anti-tumor therapeutic agent on cardiac cells, tissue or cardiac function that results in the inhibition, reduction or loss of one or more functions of the heart, e.g. , cardiac impairment.
  • the inhibition, reduction or loss of one or more cell functions refers to the loss of, or inhibition of, a cell's ability to replicate (e.g. , proliferate) and/or undergo mitosis or meiosis.
  • the inhibition, reduction or loss of one or more cell functions refers to the loss of, or inhibition of, a cell's ability to metabolize oxygen, proteins, fatty acids, carbohydrates and/or glucose.
  • the inhibition, reduction or loss of one or more cell functions refers to the loss of, or inhibition of, a cell's ability to initiate, or maintain contraction function or activity. In some embodiments the inhibition, reduction or loss of one or more cell functions refers to the loss of, or inhibition of, a cell's ability to initiate or respond to an electrical signal.
  • an anti-cancer or anti-tumor therapeutic agent causes, promotes, increases or induces cell death or apoptosis of a cardiac cell.
  • Cell death can be any type of cell death that is induced by any known or unknown mechanism.
  • cell death refers to apoptotic death (e.g. , apoptosis), autophagic cell death (autophagy) and/or necrotic cell death (e.g. , necrosis).
  • cell death refers to a loss of cell viability.
  • Cell death and/or viability can be determined by a suitable assay known in the art or described herein. Non-limiting examples include cardiac function, contractile function or electrical signal responsiveness.
  • Additional assays include membrane alteration assay (e.g. , as measured by annexin-V binding, uptake of impermeable dyes such as propidium iodide, trypan blue, LDH release, the like or combinations thereof), caspase activation assays (e.g. , as measured by peptide substrate cleavage, substrate cleavage (e.g. , PARP, M30), caspase processing, the like or combinations thereof), DNA fragmentation assays (e.g. , TUNEL assay, or assessment of DNA laddering, cytoplasmic nucleosomes, hypodiploid DNA, and release of incorporated nucleotides (e.g.
  • membrane alteration assay e.g. , as measured by annexin-V binding, uptake of impermeable dyes such as propidium iodide, trypan blue, LDH release, the like or combinations thereof
  • caspase activation assays e.g. , as measured by peptid
  • Cardiac cytotoxicity, impairment of cardiac function and/or impairment or death of cardiac cells can be induced by an anti-cancer or anti-tumor therapeutic agent. Cardiac cytotoxicity, impairment of cardiac function and/or impairment or death of cardiac cells can be induced when a cardiac cell comes into contact with one or more anti -cancer or anti-tumor therapeutic agents.
  • an anti-cancer or anti-tumor therapeutic agent is cytotoxic to a cardiac cell.
  • administration of an anti-cancer or antitumor therapeutic agent to a subject induces, causes, promotes, increases and/or stimulates cardiac cytotoxicity, impairment of cardiac function and/or impairment or death of cardiac cells.
  • Cardiac cytotoxicity, impairment of cardiac function and/or impairment or death of cardiac cells can occur or is worse in the absence of a method described herein (e.g. , in the absence of administering humanin or a humanin analog).
  • administration of an anti-cancer or anti-tumor therapeutic agent to a subject reduces, decreases, or inhibits maturation, proliferation and/or survival of cardiac cells in the absence of a method described herein (e.g. , in the absence of administering humanin or a humanin analog).
  • administration of an anti-cancer or antitumor therapeutic agent to a subject damages cardiac cells or cardiac function in the absence of a method described herein (e.g. , in the absence of administering humanin or a humanin analog).
  • Cell damage may include damage to genomic DNA, mitochondria or other organelles, mitochondrial DNA, mitochondrial cell walls or phospholipid membranes.
  • Anti-cancer or anti-tumor therapeutic agents can include a variety of poisons, venoms, toxins, proteins, antibodies and inhibitors that can cause, promote or induce impairment of cardiac function and/or death of a cardiac cells by a variety of mechanisms.
  • poisons, venoms, toxins, proteins, antibodies and inhibitors that can cause, promote or induce impairment of cardiac function and/or death of a cardiac cells by a variety of mechanisms.
  • a therapeutic agent comprises a cytotoxic compound.
  • Cytotoxic compound can induce cell death of cardiac cells, damage cardiac cells and/or inhibit one or more functions of cardiac cells.
  • Cytotoxic compounds can be organic compounds.
  • cytotoxic compounds are small organic compounds with a molecular weight between 1 and about 5000 Daltons, 1 and about 2500 Daltons, 1 and about 1000 Daltons, 1 and about 500 Daltons or between about 50 and about 1000 Daltons.
  • Anti-cancer or anti-tumor therapeutic agents can be monoclonal or polyclonal antibodies. Anti-cancer or anti-tumor therapeutic agents can be polypeptides or fusion proteins. In some embodiments, Anti -cancer or anti-tumor therapeutic agents are not cytotoxic until after they are administered to a subject wherein the therapeutic agents are metabolized into a cytotoxic compound. In some embodiments a cardiac cell is contacted with an anti-cancer or anti-tumor therapeutic agent and the cardiac cell metabolizes the therapeutic agent into a cytotoxic compound. Cardiac blood cells can be contacted directly or indirectly (e.g. , by a targeted approach) with an anti-cancer or anti-tumor therapeutic agents agent.
  • Anti-cancer and/or anti-tumor therapeutic agents are often administered to a subject (e.g. , a patient) for the treatment of a hyperproliferative disease or disorder.
  • a subject e.g. , a patient
  • Anti-cancer and/or anti-tumor therapeutic agents are often administered to a subject (e.g. , a patient) for the treatment of a hyperproliferative disease or disorder.
  • anti -cancer and/or anti-tumor therapeutic agents comprise or consist of one or more cytotoxic compounds.
  • a therapeutic agent comprises a suitable
  • a therapeutic agent comprises or consists of an alkylating agent, an anthracycline, cytoskeletal disruptors, epothilones (e.g. , epothilone), histone deacetylase inhibitors (e.g. , vorinostat, romidepsin), inhibitors of topoisomerase I (e.g. , irinotecan, topotecan), inhibitors of topoisomerase II (e.g. , etoposide, teniposide, tafluposidean), kinase inhibitors, peptide antibiotics (e.g.
  • a therapeutic agent comprises a DNA intercalating agent or an agent that attaches to or bonds to DNA.
  • Non-limiting examples of alkylating agents include anthracyclines, which include doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, known analogs and derivatives thereof.
  • Non-limiting examples of cytoskeletal disruptors e.g. , taxanes
  • Non-limiting examples of biologies include Trastuzumab, Bevacizumab, Lapatinib, Alemtuzumab and Imatinib, known analogs and derivatives thereof.
  • an anti-cancer or anti-tumor therapeutic agent induces partial or complete destruction of some or all hyperproliferating cells in a subject.
  • a therapeutic agent induces partial or complete destruction of a neoplastic, tumor, cancer or malignant cell mass in a subject.
  • a therapeutic agent can decrease the volume or size of a neoplasia, neoplastic tumor, cancer or malignancy and/or reduce the numbers of hyperproliferating cells in a subject.
  • a therapeutic agent stimulates and/or induces apoptosis, necrosis, and/or lysis of hyperproliferating cells or cells of a neoplastic tumor, cancer or malignant cell masses in a subject.
  • a therapeutic agent inhibits or prevents progression of or an increase in hyperproliferatmg cells or a neoplasia, tumor, cancer or malignancy.
  • a therapeutic agent prolongs lifespan of a subject comprising a hyperproliferatmg disease or disorder.
  • the efficacy or activity of a therapeutic agent can be determined according to 1) its ability and effectiveness to induce partial or complete destruction of some or all hyperproliferatmg cells in a subject, 2) induce partial or complete destruction of a neoplastic, tumor, cancer or malignant cell mass in a subject, 3) decrease the volume or size of a neoplasia, neoplastic tumor, cancer or malignancy and/or reduce the numbers of hyperproliferatmg cells in a subject, 4) stimulate and/or induces apoptosis, necrosis, and/or lysis of hyperproliferatmg cells or cells of a neoplastic tumor, cancer or malignant cell masses in a subject, 5) inhibit or prevent progression of or an increase in hyperproliferatmg cells or a neoplasia, tumor, cancer or malignancy in a subject, and/or 6) prolong the lifespan of a subject comprising a
  • the administration of humanin or a humanin analog does not substantially reduce, decrease, suppress or inhibit efficacy or activity of an anti-cancer or anti-tumor therapeutic agent.
  • a method, use or composition herein protects or preserves cardiac function.
  • protection or preservation of cardiac function is from an anti-cancer or anti-tumor therapeutic agent.
  • compositions, uses and methods herein are used to treat subjects suspected of having, diagnosed with and/or being treated for a hyperproliferative disease or disorder.
  • a hyperproliferative disease or disorder refers to a neoplasia, tumor, cancer or malignancy.
  • a hyperproliferative disease or disorder refers to a subject having a neoplasia, tumor, cancer or malignancy.
  • a hyperproliferative disease or disorder can be metastatic, non-metastatic or benign.
  • a neoplasia, tumor, cancer or malignancy comprises a solid cellular mass.
  • a malignant neoplasm comprises or consist of a fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, malignant fibrous histiocytoma, hemangiosarcoma, angiosarcoma, lymphangiosarcoma, mesothelioma,
  • leiomyosarcoma rhabdomyosarcoma, squamous cell carcinoma, epidermoid carcinoma, malignant skin adnexal tumor, adenocarcinoma, hepatoma, hepatocellular carcinoma, renal cell carcinoma, hypernephroma, cholangiocarcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal cell carcinoma, glioma, glioblastoma multiforme, neuroblastoma, medulloblastoma, malignant meningioma, malignant schwannoma, neurofibrosarcoma, parathyroid carcinoma, medullary carcinoma of thyroid, bronchial carcinoid, oat cell carcinoma, malignant pheochromocytoma, islet cell carcinoma, malignant carcinoid, retinoblastoma, chemodectoma, paraganglioma, malignant carcinoid, malignant paragangli
  • a neoplasia, tumor, cancer or malignancy comprises a carcinoma, sarcoma, lymphoma, leukemia, adenoma, adenocarcinoma, melanoma, glioma, glioblastoma, Kaposi sarcoma, meningioma, neuroblastoma, retinoblastoma, astrocytoma, oligodendrocytoma, reticuloendothelial, lymphatic or haematopoietic neoplasia, tumor, cancer or malignancy.
  • a sarcoma comprises a lymphosarcoma, liposarcoma, osteosarcoma, chondrosarcoma, leiomyosarcoma, rhabdomyosarcoma or fibrosarcoma.
  • a hyperproliferative disease or disorder comprises
  • a haematopoietic cell neoplasia, tumor, cancer or malignancy comprises a myeloma, lymphoma or leukemia.
  • a leukemia is an acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), or chronic myelomonocytic leukemia (CMML).
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • CMML chronic myelomonocytic leukemia
  • a neoplasia, tumor, cancer or malignancy comprises a metastatic melanoma.
  • a neoplasia, tumor, cancer or malignancy comprises a lung, thyroid, head or neck, nasopharynx, throat, nose or sinuses, brain, spine, breast, adrenal gland, pituitary gland, thyroid, lymph, gastrointestinal (mouth, esophagus, stomach, duodenum, ileum, jejunum (small intestine), colon, rectum), genitourinary tract (uterus, ovary, cervix, endometrial, bladder, testicle, penis, prostate), kidney, pancreas, liver, bone, bone marrow, lymph, blood, muscle, or skin, lung, biliary tract, or hematologic neoplasia, tumor, or cancer.
  • methods, uses and compositions described herein are to treat a subject having undergone surgical resection, chemotherapy, immunotherapy, ionizing or chemical radiotherapy, local or regional thermal (hyperthermia) therapy, or vaccination.
  • uses and compositions described herein are not used to treat a subject having undergone surgical resection, chemotherapy, immunotherapy, ionizing or chemical radiotherapy, local or regional thermal (hyperthermia) therapy, or vaccination.
  • uses and compositions described herein are not used to treat a subject that is a candidate for surgical resection, chemotherapy, immunotherapy, ionizing or chemical radiotherapy, local or regional thermal (hyperthermia) therapy, or vaccination.
  • a method, use or composition described herein protects cardiac cells in a subject from suppression and/or death. In some embodiments a method, use or composition described herein protects cardiac cells in a subject from an anti-cancer or anti-tumor therapeutic agent. Without being limited by theory, a method, use or composition described herein may protect cardiac cells by preserving viability and/or function from the deleterious effects (e.g. , adverse effects) caused by administration of an anti-cancer or anti-tumor therapeutic agent.
  • the term "protect” can mean to prevent, shelter, shield and/or insulate.
  • a method, use or composition described herein may inhibit cardiac cell necrosis, autophagy or apoptosis induced by administration of a therapeutic agent (e.g. , a cytotoxic compound).
  • a method, use or composition described herein may inhibit certain signaling pathways that may lead to apoptosis where the apoptotic pathway is activated by an anti-cancer or anti-tumor therapeutic agent.
  • a method, use or composition described herein may inhibit cardiac cell senescence.
  • a method, use or composition described herein reduces, decreases, or inhibits cardiotoxicity induced by a therapeutic agent by up to 100%, up to 50%, up to 30%, up to 20%, up to 15%, up to 10%, or up to 5%.
  • a method or composition described herein reduces, decreases, or inhibits cardiac cell death caused, induced or promoted by an anti-cancer or anti-tumor therapeutic agent by at least 200%, at least 150%, at least 100%, at least 50%, at least 30%, at least 20%, at least 15%, at least 10%, or at least 5%.
  • a method, use or composition described herein decreases, reduces or inhibits impairment of cardiac function induced or promoted by an anti -cancer or anti-tumor therapeutic agent by at least 200%, at least 150%, at least 100%, at least 50%, at least 30%, at least 20%, at least 15%, at least 10%, or by at least 5%.
  • a method, use or composition described herein promotes and/or increases maturation, proliferation and/or survival of cardiac cells in a subject. In some embodiments a method, use or composition described herein promotes and/or increases maturation, proliferation and/or survival of cardiac cells in a subject administered an anti-cancer or anti -tumor therapeutic agent. In some embodiments administration or delivery of humanin or a humanin analog promotes and/or increases maturation, proliferation and/or survival of cardiac cells in a subject administered an anti-cancer or anti-tumor therapeutic agent.
  • administering reduces, decreases, or inhibits maturation, proliferation and/or survival of cardiac cells in the absence of administration or delivery of humanin or humanin analog, which reduction, decrease or inhibition can be completely or partially reversed by administration of humanin or a humanin analog.
  • a method, use or composition described herein promote and/or increase maturation, proliferation and/or survival of cardiac cells by up to 200%, up to 100%, up to 50%, up to 30%, up to 20%, up to 15%, up to 10%, or up to 5%.
  • a method, use or composition described herein reduces, decreases, or inhibits cardiac mortality.
  • a method, use or composition described herein protects or preserves cardiac function in the presence of an anti-cancer or antitumor therapeutic agent.
  • a method, use or composition described herein reduces, decreases, or inhibits impairment of cardiac function as determined by an assay, such as an electrocardiogram, magnetic resonance imaging (MRI) or computerized tomography (CT) scan, in a subject that was administered or delivered an anti -cancer or anti-tumor therapeutic agent.
  • an assay such as an electrocardiogram, magnetic resonance imaging (MRI) or computerized tomography (CT) scan
  • a method, use or composition herein comprises humanin or a humanin analog.
  • a method or use includes administering or delivery of humanin or a humanin analog to subject.
  • Humanin or a humanin analog can be administered or delivered to a subject prior to, during or after administration of an anti -cancer or anti-tumor therapeutic agent.
  • Humanin or a humanin analog can be administered to a subject prior to, during or after treatment with an anti-cancer or anti-tumor therapeutic agent.
  • humanin or a humanin analog is administered or delivered to a subject prior to onset of cardiotoxicity.
  • humanin or a humanin analog is administered or used prior to, substantially contemporaneously with or following administration of an anti -cancer or anti-tumor therapeutic agent. In certain embodiments humanin or a humanin analog is administered or used in combination with an anti-cancer or anti-tumor therapeutic agent.
  • human comprises the amino acid sequence of SEQ ID NO: l.
  • a humanin analog can be a humanin variant. Exemplary non-limiting examples of humanin analogs and/or variants applicable to the methods, uses and compositions set forth herein are shown and described in Tables 1 to 4.
  • administration or delivery of humanin or a humanin analog reduces, decreases or inhibits damage to cardiac cells or cardiac tissue.
  • humanin or a humanin analog is administered or delivered in an amount sufficient to reduce, decrease, or inhibit cardiotoxicity caused by the anti-cancer or anti-tumor therapeutic agent.
  • humanin or a humanin analog is administered or delivered in an amount sufficient for protecting or preserving cardiac function in the presence of an anti -cancer or antitumor therapeutic agent.
  • humanin or a humanin analog is administered or delivered in an amount sufficient to reduce, decrease, or inhibit cardiac mortality in a subject (e.g. , a subject treated with an anti-cancer or anti-tumor therapeutic agent).
  • humanin or a humanin analog is administered or delivered in an amount sufficient to reduce, decrease, or inhibit impairment of cardiac function in a subject (e.g. , a subject treated with an anti-cancer or anti-tumor therapeutic agent).
  • humanin or a humanin analog decreases, or inhibits impairment of cardiac function as determined by an electrocardiogram, magnetic resonance imaging (MRI) or computerized tomography (CT) scan; or reduces, decreases, or inhibits cardiac function impairment which comprises decrease in ejection fraction and/or fractional ventricular shortening.
  • humanin or a humanin analog restores, stabilizes, inhibits or prevents a reduction or decrease in ejection fraction and/or fractional ventricular shortening caused or induced by the anti -cancer or anti-tumor therapeutic agent.
  • Methods of determining cardiotoxicity, damage to cardiac cells or cardiac tissue and impairment of cardiac function are known to the skilled artisan.
  • any suitable method can be used to determine, measure and/or assess cardiotoxicity, heart damage, damage to cardiac cells or cardiac tissue and impairment of cardiac function, non-limiting examples of which include chest X-rays, electrocardiogram (e.g., EKG or ECG), blood tests, physical examination (e.g., vitals, heart rate, blood pressure, etc.), exercise stress test, patient survey (e.g., to assess pain, angina, etc.), magnetic resonance imaging (MRI), computerized tomography (CT) scan, radionuclide ventriculography, multiple-gated acquisition scanning, cardiac catheterization, the like or combinations thereof.
  • an amount of cardiotoxicity in a subject can readily be determined and/or measured.
  • a reduction, decrease, inhibition, increase, or stabilization of cardiotoxicity in a subject can be determined and/or measured using a suitable method by measuring and/or assessing an amount of cardiotoxicity before, after and/or during a treatment.
  • compositions, methods and uses of the invention can be administered or delivered prior to, contemporaneously with or after an anti-cancer or anti-tumor therapeutic agent is administered or delivered, for example to a subject. Accordingly, methods, uses and compositions of the invention can be delivered prior to cardiotoxicity, damage to cardiac cells or cardiac tissue or impairment of cardiac function in order to protect or preserve cardiac cells.
  • "Prophylaxis" and grammatical variations thereof mean a method in which contact, administration or in vivo delivery to a subject is prior to administration or delivery of an anticancer or anti-tumor therapeutic agent, or prior to cardiotoxicity, damage to cardiac cells or cardiac tissue, or impairment of cardiac function.
  • subjects are candidates for invention compositions, methods and uses, but the subject may not yet exhibit cardiotoxicity, damage to cardiac cells or cardiac tissue, or impairment of cardiac function.
  • compositions, methods and uses can provide a detectable or measurable reduction, decrease, or inhibition of damage to cardiac cells or cardiac tissue, increase or stabilization of cardiac function, and/or reduce, decrease, or inhibit cardiac mortality of a subject.
  • Compositions, methods and uses of the invention therefore include providing a therapeutic benefit or improvement to a subject, for example, as reflected by cardiac cell damage or heart function/impairment or mortality.
  • compositions, methods and uses of the invention can be administered or delivered in a sufficient or effective amount to a subject.
  • An "effective amount” or “sufficient amount” refers to an amount that provides, in single or multiple doses, alone or in combination, with one or more other compositions (e.g. , therapeutic agents or drugs), treatments, protocols, or therapeutic regimens, a detectable response of any duration of time (long or short term), an expected or desired outcome in or a benefit to a subject of any measurable or detectable degree or for any duration of time (e.g., for minutes, hours, days, months, years, or cured).
  • a sufficient amount humanin or a humanin analog comprises an amount between about 0.01 to 100 mg/Kg (mg of humanin or a humanin analog per Kg of a subjects body weight) per day, between about 0.05 to 50 mg/Kg per day, between about 0.1 to 25 mg/Kg per day, between about 0.5 to 15 mg/Kg per day, between about 0.5 to 15 mg/Kg per day, or between about 1.0 to 10 mg/Kg per day.
  • administering a sufficient amount of humanin or a humanin analog comprises administered one or more dose amounts of between about 0.01 to 100 mg/Kg per day, between about 0.05 to 50 mg/Kg per day, between about 0.1 to 25 mg/Kg per day, between about 0.5 to 15 mg/Kg per day, between about 0.5 to 15 mg/Kg per day, or between about 1.0 to 10 mg/Kg per day.
  • a sufficient amount of humanin or a humanin analog may be administered in 1 , 2, 3, 4, 5, 6, or 7 doses per day.
  • a sufficient amount of humanin or a humanin analog is administered continuously or intermittently by a patch or suitable device (e.g. , a pump).
  • a sufficient amount of humanin or a humanin analog may be self-administered by a subject. For example a subject may use, in one or more doses, a sufficient amount of humanin or a humanin analog.
  • an effective amount or a sufficient amount can but need not be provided in a single administration, may require multiple administrations, and, can but need not be, administered alone or in combination with another composition (e.g. , agent), treatment, protocol or therapeutic regimen.
  • the amount may be proportionally increased as the amount of an anticancer or anti-tumor therapeutic agent administered to the subject increases and the anticipated or predicted cardiotoxicity, damage to cardiac cells or cardiac tissue, cardiac impairment or cardiac mortality.
  • the probability or occurrence of cardiotoxicity, damage to cardiac cells or cardiac tissue, cardiac impairment or cardiac mortality increases.
  • the amount may also be determined by the need of the subject, type, status and severity of the cardiac damage that already exists (if any).
  • an effective amount or a sufficient amount need not be effective or sufficient if given in single or multiple doses without a second composition (e.g. , another drug or agent), treatment, protocol or therapeutic regimen, since additional doses, amounts or duration above and beyond such doses, or additional compositions (e.g. , drugs or agents), treatments, protocols or therapeutic regimens may be included in order to be considered effective or sufficient in a given subject.
  • Amounts considered effective also include amounts that result in a reduction of the use of another treatment, therapeutic regimen or protocol.
  • an effective amount or a sufficient amount means effectiveness or sufficiency in a particular subject, not a group or the general population. Accordingly, appropriate amounts will depend upon the condition treated, the therapeutic effect desired, as well as the individual subject (e.g. , the bioavailability within the subject, gender, age, etc.).
  • Effectiveness of a method or use, such as a method of treatment herein can provide a potential therapeutic benefit or improvement that can be ascertained by various methods.
  • Such methods include, for example, measuring cardiac cell viability, damage to cardiac cells or cardiac tissue, heart function, and cardiac impairment. Measuring can be achieved by various means, including electrocardiogram, magnetic resonance imaging (MRI) or computerized tomography (CT) scan and/or cardiac function (e.g. , stress) tests to ascertain effectiveness of a method, use or composition as set forth herein.
  • MRI magnetic resonance imaging
  • CT computerized tomography
  • Humanin and/or humanin analogs can be packaged in a suitable pharmaceutical formulation and/or dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form refers to physically discrete units suited as unitary dosages; each unit contains a quantity of the
  • composition optionally in association with a carrier, excipient, diluent, or vehicle calculated to produce the desired treatment or therapeutic (e.g. , beneficial) effect.
  • a carrier excipient, diluent, or vehicle calculated to produce the desired treatment or therapeutic (e.g. , beneficial) effect.
  • the unit dosage forms can be varied according to factors including, but not necessarily limited to, the particular composition employed, the disorder or disease treated, the effect to be achieved, and the subject to be treated.
  • Exemplary unit doses range from about 25-250, 250-500, 500-1,000, 1,000-2,500, 2,500-5,000, 5,000-25,000, or 5,000-50,000 pg; from about 50-500, 500-5,000, 5,000-25,000 or 25,000-50,000 ng; from about 50-500, 500-5,000, 5,000-25,000 or 25,000-50,000 ⁇ g; from about 25-250, 250- 500, 500-1 ,000, 1 ,000-2,500, 2,500-5,000, 5,000-25,000, or 5,000-50,000 mg; and from about 1-5, 5-10, 10-25, 25-50, 50-100, 100-250, 250-500, 500-1 ,000, 1 ,000-2,500, or 2,500-5,000 grams.
  • humanin and/or humanin analogs and compositions thereof may be contacted or provided in vitro, ex vivo or administered or delivered in vivo to a subject or patient in various doses and amounts, and frequencies.
  • a humanin and/or humanin analog or a composition thereof can be administered or delivered to provide the intended effect, as a single or as multiple dosages, for example, in an effective or sufficient amount.
  • Single or multiple (e.g. , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more times) administrations or doses can be administered on the same or consecutive days, alternating days or intermittently.
  • a humanin and/or humanin analog or a composition thereof can be administered one, two, three, four or more times daily, on alternating days, bi-weekly, weekly, monthly, bi-monthly, or annually.
  • a humanin and/or humanin analog or composition thereof can be administered for any appropriate duration, for example, for period of 1 hour, or less, e.g. , 30 minutes or less, 15 minutes or less, 5 minutes or less, or 1 minute, or less.
  • a humanin and/or humanin analog or composition thereof can be administered to a subject and methods and uses may be practiced prior to, substantially contemporaneously with, or within about 1-60 minutes, hours (e.g. , within 1, 2, 3, 4 , 5, 6, 8, 12, 24 hours), or days (1 , 2, 3, 4, 5, 6, 7, 7-14, 14-21, 21-28, 28-45, 45-60, 60-90, etc.) of administration of an anti-cancer or antitumor therapeutic agent.
  • a humanin and/or humanin analog or composition thereof can be administered or delivered and methods and uses may be practiced via systemic, regional or local administration, by any route.
  • a humanin and/or humanin analog or composition thereof may be administered or delivered systemically, regionally or locally, via injection, infusion, orally (e.g. , ingestion or inhalation), topically, intravenously, intra-arterially, intramuscularly,
  • Humanin and/or humanin analog, compositions, methods and uses of the invention including pharmaceutical formulations may be administered via a (micro) encapsulated delivery system or packaged into an implant for administration.
  • Humanin and/or humanin analog or composition thereof can be incorporated into pharmaceutical compositions, e.g. , a pharmaceutically acceptable carrier or excipient.
  • pharmaceutical compositions are useful for, among other things, administration and delivery to a subject in vivo or ex vivo.
  • the term "pharmaceutically acceptable” and “physiologically acceptable” mean a biologically acceptable formulation, gaseous, liquid or solid, or mixture thereof, which is suitable for one or more routes of administration, in vivo delivery or contact.
  • a “pharmaceutically acceptable” or “physiologically acceptable” composition is a material that is not biologically or otherwise undesirable, e.g. , the material may be administered to a subject without causing substantial undesirable biological effects.
  • such a pharmaceutical composition may be used, for example in a formulation for administering or delivering a humanin and/or humanin analog or composition thereof to a subject.
  • compositions include solvents (aqueous or non-aqueous), solutions (aqueous or non-aqueous), emulsions (e.g. , oil-in-water or water-in-oil), suspensions, syrups, elixirs, dispersion and suspension media, coatings, isotonic and absorption promoting or delaying agents, compatible with pharmaceutical administration or in vivo contact or delivery.
  • Aqueous and nonaqueous solvents, solutions and suspensions may include suspending agents and thickening agents.
  • Such pharmaceutically acceptable carriers include tablets (coated or uncoated), capsules (hard or soft), microbeads, powder, granules and crystals.
  • Supplementary active compounds e.g., preservatives, antibacterial, antiviral and antifungal agents
  • compositions can be formulated to be compatible with a particular route of administration or delivery, as set forth herein or known to one of skill in the art.
  • pharmaceutical compositions include carriers, diluents, or excipients suitable for administration by various routes.
  • compositions suitable for parenteral administration comprise aqueous and nonaqueous solutions, suspensions or emulsions of the active compound, which preparations are typically sterile and can be isotonic with the blood of the intended recipient.
  • Non-limiting illustrative examples include water, saline, dextrose, fructose, ethanol, animal, vegetable or synthetic oils.
  • penetrants can be included in the pharmaceutical composition.
  • Penetrants are known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • the active ingredient can be formulated into aerosols, sprays, ointments, salves, gels, or creams as generally known in the art.
  • pharmaceutical compositions typically include ointments, creams, lotions, pastes, gels, sprays, aerosols, or oils.
  • Carriers which may be used include petroleum jelly, lanolin, polyethylene glycols, alcohols, transdermal enhancers, and combinations thereof.
  • Cosolvents and adjuvants may be added to the formulation.
  • cosolvents contain hydroxyl groups or other polar groups, for example, alcohols, such as isopropyl alcohol; glycols, such as propylene glycol, polyethyleneglycol, polypropylene glycol, glycol ether; glycerol; polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
  • Adjuvants include, for example, surfactants such as, soya lecithin and oleic acid; sorbitan esters such as sorbitan trioleate; and polyvinylpyrrolidone.
  • compositions and delivery systems are known in the art (see, e.g. , Remington: The Science and Practice of Pharmacy (2003) 20 th ed., Mack Publishing Co., Easton, PA; Remington's Pharmaceutical Sciences (1990) 18 th ed., Mack Publishing Co., Easton, PA; The Merck Index (1996) 12 th ed., Merck Publishing Group, Whitehouse, NJ;
  • kits comprising humanin and/or humanin analogs, combination compositions and pharmaceutical formulations thereof, packaged into suitable packaging material.
  • a kit optionally includes a label or packaging insert including a description of the components or instructions for use in vitro, in vivo, or ex vivo, of the components therein. Exemplary instructions include instructions for a method, treatment protocol or therapeutic regimen.
  • packaging material refers to a physical structure housing the components of the kit. The packaging material can maintain the components sterilely, and can be made of material commonly used for such purposes (e.g. , paper, corrugated fiber, glass, plastic, foil, ampules, vials, tubes, etc.).
  • Kits can include labels or inserts.
  • Labels or inserts include "printed matter," e.g., paper or cardboard, or separate or affixed to a component, a kit or packing material (e.g., a box), or attached to an ampule, tube or vial containing a kit component.
  • Labels or inserts can additionally include a computer readable medium, optical disk such as CD- or DVD-ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic/optical storage media, FLASH media or memory type cards.
  • Labels or inserts can include identifying information of one or more components therein, dose amounts, clinical pharmacology of the active ingredient(s) including mechanism of action, pharmacokinetics (PK) and pharmacodynamics (PD). Labels or inserts can include information identifying manufacturer information, lot numbers, manufacturer location and date.
  • Labels or inserts can include information on a condition, disorder, disease or symptom for which a kit component may be used.
  • Labels or inserts can include instructions for the clinician or for a subject for using one or more of the kit components in a method, treatment protocol or therapeutic regimen. Instructions can include dosage amounts, frequency or duration, and instructions for practicing any of the methods or uses, treatment protocols or therapeutic regimes set forth herein. Kits of the invention therefore can additionally include labels or instructions for practicing any of the methods and uses of the invention described herein.
  • Labels or inserts can include information on any benefit that a component may provide, such as a prophylactic or therapeutic benefit. Labels or inserts can include information on potential adverse side effects, such as warnings to the subject or clinician regarding situations where it would not be appropriate to use a particular composition. Adverse side effects could also occur when the subject has, will be or is currently taking one or more other medications that may be incompatible with the composition, or the subject has, will be or is currently undergoing another treatment protocol or therapeutic regimen which would be incompatible with the composition and, therefore, instructions could include information regarding such
  • Kits can additionally include other components. Each component of the kit can be enclosed within an individual container and all of the various containers can be within a single package. Invention kits can be designed for cold storage.
  • HN and HN analogs/variants that are contemplated in the invention methods, uses and compositions include the following:
  • HN Humanin
  • Variants with characteristics and cytoprotective action
  • HNG An HN derivative, which has a Gly substitution of Serl4 of HN.
  • HN derivatives can be selected from: Humanin with S 14P, P-S7 HN, P-S7/14 HN, (D-Serl4)HN, (D-Ser7)HN, (D-Ser7/14)HN, AGA-(D-Serl4)HN, AGA-(D-Serl4)HN17, EFLIVIKS -HNG, EFLIVIKS-HNA, EFLIVIKS-HN, EFLIVIKS-HNG-KKK, EFLIVIKS- (S7A)HN, and EFLIVIKS -AGA-HNG , and chimeric combinations thereof.
  • S 14P means that the S (serine) at location 14 in the wild-type HN has been replaced with P (proline).
  • P proline
  • D-Ser7 means that the Serine at location 7 has been switched (racemized) from a normal L-isomer to the D-isomer.
  • AGA-HN is a shorthand name of the HN derivative in which the Arg4 and Phe6 amino acids are substituted with Alanine to form R4A/F6A-HN (this is named for the AGA triplet at locations 4, 5, and 6 in the HN derivative.
  • HN17 is a truncated form of HN that includes 17 amino acids from Pro3 to Pro 19.
  • Cys/bXaa indicates Cys or a basic amino acid
  • (Leu/Arg) indicates Leu or Arg
  • (Gly/Ser) indicates Gly or Ser
  • Xnl , Xn2, and Xn3 independently indicate arbitrary amino acids not more than 10 residues, respectively.
  • Basic amino acids refer to amino acids in which its R group (side chain) is positively charged at pH7.0.
  • Examples of natural basic amino acids include Arg, Lys, and His.
  • amino acid sequences of a polypeptide that has Arg, Lys, or His as the basic amino acids can be represented, for example, as: Pro-Xnl-(Cys/Arg/Lys/His)-(Leu/Arg)-Xn2- Leu-Thr-(Gly/Ser)-Xn3-Pro (wherein "(Cys/Arg/Lys/His)" indicates Cys, Arg, Lys, or His;
  • (Leu/Arg) indicates Leu or Arg
  • (Gly/Ser) indicates Gly or Ser
  • Xnl, Xn2, and Xn3 independently indicate arbitrary amino acids not more than 10 residues, respectively).
  • Arg and Lys are particularly preferable as the basic amino acid at this position.
  • a polypeptide of the present invention may be a polypeptide wherein arbitrary amino acids with no more than 6 residues are added to all or any one of Xnl, Xn2, and Xn3 consisting of arbitrary amino acids of 4 residues, 2 residues, and 4 residues, respectively.
  • a sequence of Xnl includes, for example, sequences consisting of (Arg/Ala)- (Gly/Ala)-(Phe/Ala)-(Ser/Ala), and sequences with conservative substitution thereof.
  • Arg/ Ala indicates Arg or Ala ("/" indicates that it is either one of the residues; the same is indicated throughout the description herein).
  • Examples of such sequences include Arg- Gly-Phe-Ser, Ala-Gly-Phe-Ser, Arg-Ala-Phe-Ser, Arg-Gly-Ala-Ser , Arg-Gly-Phe-Ala , and so on.
  • Arg-Gly-Ala-Ala examples include Arg-Gly-Ala-Ala, Arg-Ala-Phe-Ala, Arg-Ala-Ala-Ser, Arg-Ala-Ala- Ala, Ala-Gly-Phe-Ala, Ala-Gly-Ala-Ser, Ala-Gly-Ala-Ala, Ala-Ala-Phe-Ser, Ala-Ala-Phe-Ala , Ala-Ala-Ala-Ser, Ala-Ala-Ala-Ala, and such.
  • sequence of Xn2 preferably includes, for example, sequences consisting of (Leu/Ala)- (Leu/Ala), and sequences with conservative substitution thereof.
  • sequences include Leu-Leu, Ala-Leu, Leu-Ala, and such.
  • Ala-Ala can be also exemplified as such sequences.
  • sequence of Xn3 preferably includes, for example, sequences consisting of (Glu/Ala)- (Ile/Ala)-(Asp/Ala)-(Leu/Ala), and sequences with conservative substitution thereof.
  • Such examples include Glu-Ile-Asp-Leu, Ala-Ile-Asp-Leu, Glu-Ala-Asp-Leu, Glu-Ile-Ala-Leu, Glu- Ile-Asp-Ala, and so on.
  • Glu-Ile- Ala-Ala Glu-Ala-Asp-Ala, Glu-Ala-Ala-Leu, Glu-Ala-Ala-Ala , Ala-Ile -Asp-Ala, Ala-Ile -Ala-Leu, Ala-Ile-Ala-Ala, Ala-Ala-Asp-Leu, Ala- Ala- Asp-Ala, Ala- Ala- Ala-Leu, Ala-Ala- Ala- Ala, and so on.
  • the sequences of Xnl , Xn2, and Xn3 may be selected from arbitrary combinations.
  • a humanin includes a plurality of humanin molecules.
  • reference to an anti -cancer or anti-tumor therapeutic agent includes a plurality of anti-cancer or anti-tumor therapeutic agents.
  • Reference to an integer with more (greater) or less than includes any number greater or less than the reference number, respectively.
  • a reference to less than 1 ,000 includes 999, 998, 997, etc. all the way down to the number one (1), and fractions thereof (e.g. , 0.5, 0.1, 0.05, 0.01, etc.; and less than 100, includes 99, 98, 97, etc. all the way down to the number one (1), and fractions thereof (e.g. , 0.5, 0.1 , 0.05, 0.01, etc.).
  • Reference to a range of 1-50 therefore includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc., up to and including 50, as well as 1.1 , 1.2, 1.3, 1.4, 1.5, etc., 2.1 , 2.2, 2.3, 2.4, 2.5, etc., and so forth.
  • Reference to a series of ranges includes ranges which combine the values of the boundaries of different ranges within the series.
  • ranges 11-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-75, 75-100, 100-150, 150-200, 200-250, 250-300, 300-400, 400-500, 500-750, 750-1 ,000, 1 ,000-1 ,500, 1 ,500-2,000, 2,000-2,500, 2,500-3,000, 3,000-3,500, 3,500-4,000, 4,000-4,500, 4,500-5,000, 5,500-6,000, 6,000-7,000, 7,000-8,000, or 8,000-9,000, includes ranges of 10-50, 50-100, 100- 1,000, 1 ,000-3,000, 2,000-4,000, etc.
  • the invention is generally disclosed herein using affirmative language to describe the numerous embodiments and aspects.
  • the invention also specifically includes embodiments in which particular subject matter is excluded, in full or in part, such as substances or materials, method steps and conditions, protocols, or procedures.
  • materials and/or method steps are excluded.
  • the invention is generally not expressed herein in terms of what the invention does not include aspects that are not expressly excluded in the invention are nevertheless disclosed herein.
  • B16 melanoma cells culture Mouse B16 melanoma cells were cultured in 75 cm 2 flasks and incubated at 37 °C in a humidified chamber with 5% CO 2 to generate enough cells for inoculating 10,000 cells/mouse x 40 mice . After 5-7 days culture, B16 cells were collected and cell viability determined using the Trypan Blue stain and the number of living cells were counted under microscope.
  • HNG HNG IP injection
  • DOX Doxorubicin
  • Fig. 1 shows the schedule of events for this study.
  • the mice in the DOX treated group would receive 6 weekly injections of DOX and daily injection of HNG until Day 40. Body weights and tumor cell injection site were checked 3 times per week. Echocardiogram was scheduled at day 26 and repeated at day 40. Twenty four hours after echocardiogram examination, animals were sacrificed; whole blood, plasma, epididymis, heart, lung, testis, liver, spleen, kidney, intestine, muscle, skin, and femur bone were collected. Sperm in the cauda epididymis were counted and COMET assay for DNA damage of sperm assessed. Whole blood was collected for CBC analysis and plasma saved for measurement of HNG level or other bio- parameters. Testes were fixed in Bouin's or formaldehyde for immunohistochemistry and TUNEL analyses.
  • Heart sections were saved for immunohistochemistry. Pieces of left ventricle were fixed with gluteraldehyde for later mitochondria analysis by EM. Heart was snapped frozen and stored at -80 degrees (left and right atriums plus the rest of ventricles) for molecular studies (e.g. ANP/BNP).
  • Body Weight Fig. 2 shows that the control, untreated, and HNG treatment mice gained weight. However the DOX and DOX+HNG mice started to lose weight at about day 8 to 10. At day 29, DOX group lost more weight than the mice treated with DOX+HNG (p ⁇ 0.05).
  • mice treated with DOX had significant loss in weight after the 4 th DOX injection on day 23.
  • the DOX injections were halted and the animals were observed for cardiotoxicity.
  • the DOX and DOX+HNG groups were scheduled for echocardiogram on day 32, but three mice in the DOX group died on day 31 and another on day 32 after completing the echocardiogram, another on day 33 and the 6 th died on day 37. All but one (which died on day 38) of the mice treated with DOX +HNG survived, though their weight was lower than the non- treated and HNG treated group.
  • Heart and Echocardiogram Analyses Echocardiogram was performed on three mice from each group on day 32, and the rest of the mice on days 34 and 38.
  • the weight of the heart of the DOX treated mice was significantly lower than the non-treated and HNG treated mice (p ⁇ 0.001).
  • Heart weight in the HNG+DOX group was significantly higher than the DOX only group (p ⁇ 0.05).
  • body weight ratio was not different among the groups (Fig. 3A & 3B.)
  • Cardiac function of the DOX treated mice was significantly impaired with a decrease in ejection fraction and fractional ventricular shortening compared to non-treated and HNG treated mice. Co-treatment with HNG returned these DOX induced cardiac function parameters to normal (untreated mice) (Fig. 4A & 4B).
  • HNG decreases DOX-induced weight loss and promotes survival in mice treated with DOX. HNG protects mice from the cardiotoxicity induced by DOX.
  • DOX-induced cardiotoxicity Currently there is no treatment for DOX-induced cardiotoxicity except for dexrazoxane which is recommended for patients receiving high doses of anthracyclines.
  • dexrazoxane causes significant adverse events including decreased granulocytes and platelets.
  • Co-administration of humanin or its analogs may have a potential role in ameliorating anthracycline-induced cardiomyopathy and chronic recurrent heart failure.
  • mice were used. These mice received for 8 weeks IP injections of saline daily (control), Doxorubicin (DOX 3mg/week IP for 8 injections), HNG 5mg/day IP), Dexrazoxane (DRZ 60mg/week IP at the same time as Doxorubicin) either alone or in combinations as shown in Figure 5. All animals received 8 weeks of injections. The DOX injections were stopped after 8 injections because the animals showed signs of ill health, and all treatment was stopped at week 9 and mice were sacrificed at week 10 after echocardiogram.
  • DOX injections were stopped after 8 injections because the animals showed signs of ill health, and all treatment was stopped at week 9 and mice were sacrificed at week 10 after echocardiogram.
  • Ejection fraction (EF) of the groups were not different at baseline, week and week 8 amongst the groups.
  • Dox treatment caused a highly significant decrease in EF compared to control, HNG alone, DRZ alone
  • the neurosurvival factor Humanin inhibits beta-cell apoptosis via signal transducer and activator of transcription 3 activation and delays and ameliorates diabetes in nonobese diabetic mice. Metabolism.
  • the neurosurvival factor Humanin inhibits beta-cell apoptosis via signal transducer and activator of transcription 3 activation and delays and ameliorates diabetes in nonobese diabetic mice. Metabolism. 59, 343-349.
  • cytoprotective peptide humanin is induced and neutralizes Bax after pro-apoptotic stress in the rat testis. Andrology 1, 651-659.
  • K562 cells by downregulation of P38 MAP kinase. Apoptosis 10, 963-971.
  • a reagent can mean one or more reagents) unless it is contextually clear either one of the elements or more than one of the elements is described.
  • the term "about” as used herein refers to a value within 10% of the underlying parameter (i.e., plus or minus 10%), and use of the term “about” at the beginning of a string of values modifies each of the values (i.e., "about 1, 2 and 3” refers to about 1 , about 2 and about 3).
  • a weight of "about 100 grams” can include weights between 90 grams and 110 grams.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Toxicology (AREA)
  • Cardiology (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Immunology (AREA)
  • Inorganic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions, des méthodes et des utilisations de l'humanine ou d'un analogue de l'humanine, par exemple dans le traitement d'un patient avec de l'humanine ou un analogue de l'humanine, en partie pour réduire, diminuer ou inhiber la cardiotoxicité provoquée ou induite par un agent thérapeutique anticancéreux ou antitumoral, ou pour protéger ou préserver la fonction cardiaque en présence d'un agent thérapeutique antitumoral ou anticancéreux.
PCT/US2016/050780 2015-09-09 2016-09-08 Compositions d'humanine, méthodes et utilisation pour protéger le coeur contre le stress et la chimiothérapie Ceased WO2017044626A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US15/916,204 US10792331B2 (en) 2015-09-09 2018-03-08 Methods for reducing cardiotoxicity from chemotherapy by administering humanin analog compositions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562215974P 2015-09-09 2015-09-09
US62/215,974 2015-09-09

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/916,204 Continuation-In-Part US10792331B2 (en) 2015-09-09 2018-03-08 Methods for reducing cardiotoxicity from chemotherapy by administering humanin analog compositions

Publications (1)

Publication Number Publication Date
WO2017044626A1 true WO2017044626A1 (fr) 2017-03-16

Family

ID=58240838

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/050780 Ceased WO2017044626A1 (fr) 2015-09-09 2016-09-08 Compositions d'humanine, méthodes et utilisation pour protéger le coeur contre le stress et la chimiothérapie

Country Status (1)

Country Link
WO (1) WO2017044626A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120252722A1 (en) * 2005-11-09 2012-10-04 Desmond Mascarenhas Metal-binding therapeutic peptides
US20130053323A1 (en) * 2009-12-22 2013-02-28 Emma Eriksson Methods and use related to humanin and humanin-like peptides
WO2013074871A2 (fr) * 2011-11-17 2013-05-23 Cohbar, Inc. Analogues d'humanine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120252722A1 (en) * 2005-11-09 2012-10-04 Desmond Mascarenhas Metal-binding therapeutic peptides
US20130053323A1 (en) * 2009-12-22 2013-02-28 Emma Eriksson Methods and use related to humanin and humanin-like peptides
WO2013074871A2 (fr) * 2011-11-17 2013-05-23 Cohbar, Inc. Analogues d'humanine

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
COHEN ET AL.: "New Role for the Mitochondrial Peptide Humanin: Protective Agent Against Chemotherapy-Induced Side Effects.", JNCI J NATL CANCER INST, vol. 106, no. 3, 1 March 2014 (2014-03-01), XP055224361 *
HASHIMOTO ET AL.: "A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta.", PNAS, vol. 98, no. 11, 22 May 2001 (2001-05-22), pages 6336 - 6341, XP002190962 *
MUZUMDAR ET AL.: "Acute Humanin Therapy Attenuates Myocardial Ischemia and Reperfusion Injury in Mice.", ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY, vol. 30, 15 September 2010 (2010-09-15), pages 1940 - 1948, XP055371792 *

Similar Documents

Publication Publication Date Title
Liu et al. AMPK/PGC1α activation by melatonin attenuates acute doxorubicin cardiotoxicity via alleviating mitochondrial oxidative damage and apoptosis
Nizamutdinova et al. Paeonol and paeoniflorin, the main active principles of Paeonia albiflora, protect the heart from myocardial ischemia/reperfusion injury in rats
Mahran New insights into the protection of growth hormone in cisplatin-induced nephrotoxicity: the impact of IGF-1 on the Keap1-Nrf2/HO-1 signaling
Lue et al. Humanin analog enhances the protective effect of dexrazoxane against doxorubicin-induced cardiotoxicity
US10239924B2 (en) Peptide having eight amino acid sequences derived from cage and retaining anticancer activity and activity to promote anticancer drug sensitivity of anticancer drug-resistant cancer cells
Mazevet et al. Complications of chemotherapy, a basic science update
CN105163749B (zh) 治疗骨髓性白血病的方法
CN112023054A (zh) 癌症的治疗
EP2049121B1 (fr) Compositions destinés à favoriser l'effet de thérapies anti-cancer
KR20190084291A (ko) 암 치료를 위한 제약 조성물 및 방법
He et al. Growth inhibition and apoptosis induced by lupeol, a dietary triterpene, in human hepatocellular carcinoma cells
Ahmed et al. Repurposing of metformin for cancer therapy: Updated patent and literature review
US10792331B2 (en) Methods for reducing cardiotoxicity from chemotherapy by administering humanin analog compositions
US9937227B2 (en) Humanin, analogs and cancer treatment methods and uses thereof
Wolfson et al. Enhancing FTS (Salirasib) efficiency via combinatorial treatment
Hiraumi et al. Granulocyte colony-stimulating factor protects cardiac mitochondria in the early phase of cardiac injury
US20170216399A1 (en) Compositions, methods and uses for protecting white blood cells from suppression or death
EP3697387A1 (fr) Combinaison d'as1411 et de sapc-dops pour le traitement du glioblastome multiforme
Leung et al. PEGylated recombinant human arginase as a drug for breast cancer
Hamaamin et al. Doxorubicin-induced cardiotoxicity: Mechanisms and management
WO2017044626A1 (fr) Compositions d'humanine, méthodes et utilisation pour protéger le coeur contre le stress et la chimiothérapie
KR20200094110A (ko) 스트렙토니그린 및 항암제를 포함하는 뇌종양 예방 또는 치료용 조성물
US9333212B2 (en) Proteasome inhibitors as ovoprotective agents to shield the ovary from chemotherapy toxicity
US20220202804A1 (en) Compositions and methods to treat cancer
KR101824205B1 (ko) 암 예방 또는 치료용 약학적 조성물 및 이의 용도

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16845052

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16845052

Country of ref document: EP

Kind code of ref document: A1